There is an urgent need for more effective drug delivery agents for treatment of brain tumors, which are among the most aggressive and intractable cancers. SapC-DOPS, a nanovesicle composed of saposin C (SapC) coupled to dioleoylphosphatidylserine (DOPS), has proven tumor targeting properties, which include crossing the blood-brain tumor barrier and binding the lipid tumor marker, extracellular phosphatidylserine (PS). It also exhibits antitumor activities in preclinical glioblastoma (GBM) models. We hypothesize that endowing SapC-DOPS nanovesicles with a radiolabeled lipophilic reporter will create a novel agent with superior efficacy for targeted radionuclide therapy (TRT) of GBMs. Treatment options for GBMs are very limited, and standard therapies with radiation and/or chemotherapy provide only modest survival benefits with potential deleterious effects. To address these issues, we propose to create a novel cancer-selective, targeted radiolabeled SapC-DOPS for TRT of GBMs. A unique advantage of MTTI's approach lies in the feedforward therapeutic mechanism of the novel compound: radiation exposure is known to increase PS externalization in tumor cells, thus leading to enhanced anticancer effects by PS-targeted SapC-DOPS nanovesicles. This proposal is backed by extensive, published and unpublished, preliminary data, the FDA Orphan Drug designation of SapC-DOPS, and an ongoing clinical phase I trial.